Upregulated IL-18 expression in type 2 diabetic subjects with nephropathy: TGF-β1 enhanced IL-18 expression in human renal proximal tubular epithelial cells

Aim: In order to clarify the importance of Interleukin (IL)-18 in the development of diabetic nephropathy (DN), we evaluated the expressions of IL-18 in diabetic kidney. Methods: We per-formed immmunohistochemical analysis of IL-18 and IL-18 receptor (IL-18 R) in human kidney tissue derived from 12 subjects with type 2 diabetes and overt nephropathy, and compared with those in 7 subjects with minimal change nephrotic syndrome (MCNS). In addition, we examined the regulation of IL-18 expression using human renal proximal tubular epithelial cells (HRPTECs) in culture. Results: IL-18 expression in tubular cells was observed in higher rate (83%) in patients with diabetes, whereas one positive specimen (14.3%) for IL-18 in patients with MCNS. In contrast, IL-18 R was expressed in glomerular mesangial cells and endothelial cells as well as tubular cells, similarly in almost of both groups. Exposure to transforming growth factor beta (TGF-beta(1)) led to two-fold increase in IL-18 gene expression in HRPTECs, and mitogen-activated protein kinases (MAPK) inhibitors abolished TGF-beta(1)-induced IL-18 mRNA expression. Western blot analysis showed the IL-18 protein in HRPTECs. Conclusion: The present data indicate that IL-18 is overexpressed in human tubular epithelial cells in diabetic nephropathy, probably through the activation of MAPK pathways induced by TGF-beta(1). (C) 2008 Elsevier Ireland Ltd. All rights reserved.